Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related ...to mutations in genes
and
(encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of
and
-related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.
Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ...ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP.
All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale CAJIS and the FOP-Physical Function Questionnaire FOP-PFQ) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed.
Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm
/year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52).
Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients.
This study ( NCT02322255 ) was first posted on 23 December, 2014.
Stüve-Wiedemann syndrome (SWS) is characterised by bowing of the lower limbs, respiratory distress and hyperthermia that are often responsible for early death. Survivors develop progressive scoliosis ...and spontaneous fractures. We previously identified
mutations in most SWS cases, but absence of
pathogenic changes in five patients led us to perform exome sequencing and to identify homozygosity for a
mutation in one case p.Ser205Tyrfs*13. The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae.
This prompted us to screen
in 25 OI patients with no known mutations.We identified a homozygous deleterious variant in
in two affected sibs with typical OI p.His127Arg. Another homozygous variant, p.Asp231Gly, also classed as deleterious, was detected in a patient with type III OI of consanguineous parents using homozygosity mapping and exome sequencing.FAM46A is a member of the superfamily of nucleotidyltransferase fold proteins but its exact function is presently unknown. Nevertheless, there are lines of evidence pointing to a relevant role of FAM46A in bone development. By RT-PCR analysis, we detected specific expression of
in human osteoblasts andinterestingly, a nonsense mutation in
has been recently identified in an ENU-derived (
-ethyl-
-nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities and reduced cortical thickness in long bones.
We conclude that
mutations are responsible for a severe form of OI with congenital bowing of the lower limbs and suggest screening this gene in unexplained OI forms.
Clinical Features of Lysosomal Acid Lipase Deficiency Burton, Barbara K.; Deegan, Patrick B.; Enns, Gregory M. ...
Journal of pediatric gastroenterology and nutrition,
2015-December, Volume:
61, Issue:
6
Journal Article
Peer reviewed
Open access
Objective:
The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.
Methods:
Investigators reviewed medical records of ...LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.
Results:
A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease‐related abnormality was 9.0 years (range 0–42); mean age at diagnosis was 15.2 years (range 1–46). Twenty‐nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low‐density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid‐lowering therapies, and 44% had high‐density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ~1.15 multiples of normal (MN) and median spleen volume was ~2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9–43.5 years).
Conclusion:
This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.
Schimke Immuno-Osseous Dysplasia (SIOD) is an autosomal recessive multisystem disorder caused by pathogenic variants in the gene SMARCAL1. The clinical picture is characterized by spondyloepiphyseal ...dysplasia resulting in growth failure, nephropathy and T-cell deficiency. Neurologic manifestations include microcephaly, cognitive impairment, migraine-like headaches and cerebrovascular manifestations such as cerebral atherosclerotic vascular disease and reversible cerebral vasoconstriction. The role of SMARCAL1 deficiency in non-vascular neurological complications is still under debate. Epilepsy has been reported in a few patients, even in the absence of brain abnormalities. Data regarding electroencephalographic (EEG) patterns in SIOD are scarce
We describe the clinical, neuroradiological and EEG findings in two unrelated patients with SIOD showing a peculiar pseudo-periodic EEG pattern apparently not related to the cerebrovascular complications, since it was recognized both before and after cerebrovascular events
Our observations support the hypothesis that SMARCAL1plays an important role in neurodevelopment and brain function and expand the spectrum of neurological abnormalities related to SIOD.
ABSTRACT
Background: Bone disease is a serious complication of Gaucher disease. Untreated, it can result in pain, permanent bone damage and disability. Enzyme replacement therapy reverses many of the ...clinical signs of Gaucher bone disease but early assessment and treatment, and regular monitoring, are essential in optimising outcomes.
Scope: In September 2005, a group of European experts met to review current knowledge and identify best practice and unmet needs in the monitoring of Gaucher bone disease and the response to enzyme replacement therapy.
Methods: Medline searches of peer-reviewed literature (no date restrictions) were conducted and supplemented by additional information considered relevant by panellists to furthering discussions.
Findings and conclusions: The group's recommendations included: currently used biochemical bone markers are not clinically practical or reliable; plain X‐rays should not be the sole method of assessing bone disease; MRI is the most sensitive method for monitoring bone marrow infiltration by Gaucher cells; semi-quantitative methods for assessing bone marrow infiltration in routine clinical practice should use readily available technology, include an assessment of Gaucher cell infiltration in the lumbar spine and femur, and be validated for inter-rater reliability and in comparison to other methods; a multidisciplinary approach is required for the treatment of Gaucher patients; all Gaucher patients should receive a comprehensive initial radiologic evaluation for bone disease and ongoing radiological monitoring at least once every 2 years.
GD and ASMD are lysosomal storage disorders that enter into differential diagnosis due to the possible overlap in their clinical manifestations. The availability of safe and effective enzymatic ...therapies has recently led many investigators to develop and validate new screening tools, such as algorithms, for the diagnosis of LSDs where the lack of disease awareness or failure to implement newborn screening results in a delayed diagnosis.
the proposed algorithm allows for the clinical and biochemical differentiation between GD and ASMD. It is based on enzyme activity assessed on dried blood spots by multiplexed tandem mass spectrometry (MS/MS) coupled to specific biomarkers as second-tier analysis.
we believe that this method will provide a simple, convenient and sensitive tool for the screening of a selected population that can be used by pediatricians and other specialists (such as pediatric hematologists and pediatric hepatologists) often engaged in diagnosing these disorders.
Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data ...shows a close relationship between clinical outcome and patients' cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants.
A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002-January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months).
Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients.
These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.
The 2017 classification of Ehlers‐Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, ...patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re‐define this OI/EDS overlap as a missing EDS type. Twenty‐one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS‐related features. OI‐related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N‐proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.
COL1‐relatedoverlap disorder: a novel connective tissue disorder incorporating theosteogenesis imperfecta/Ehlers‐Danlos syndrome overlap.
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